EP2066640A2

EP2066640A2 - 2-(1-oxo-1h-isoquinolin-2-yl) acetamide derivatives

Info

Publication number: EP2066640A2
Application number: EP07842137A
Authority: EP
Inventors: Jeffrey Letourneau; Jui Hsiang Chan; Patrick Jokiel; Michael Ohlmeyer; Irina Neagu; Christopher Mark Riviello; John Richard Morphy; Susan Elizabeth Napier; Koc-Kan Ho
Original assignee: Organon NV
Current assignee: Merck Sharp and Dohme BV; Pharmacopeia LLC
Priority date: 2006-09-11
Filing date: 2007-09-10
Publication date: 2009-06-10
Anticipated expiration: 2027-09-10
Also published as: US7906504B2; WO2008033757A2; AR062734A1; ATE523493T1; US20080064678A1; EP2066640A4; JP5271909B2; CA2663193A1; MX2009002685A; JP2010502745A; EP2066640B1; CN101528703A; CN101528703B; WO2008033757A3

Abstract

The present invention relates to a 2-(1-oxo-IH-isoquinolin-2-yl)acetamide derivative of formula (I).

Description

2-(1 -OXO-1 mSOQUINOLIN^-YLOACETAMIDE DERIVATIVES

The present invention relates to 2-(1-oxo-1 /-/-isoquinolin-2-yl)acetamide derivatives, to pharmaceutical compositions comprising these compounds and to their use in therapy, in particular to their use for the manufacture of a medicament for the treatment or prevention of disorders or diseases influenced by modulation of the activity of the HPA axis.

The hypothalamo-pituitary-adrenal (HPA) axis is the major stress axis in humans and other mammals. A variety of stressors (and multiple other classes of stimuli) cause release of the hormone ACTH (adrenocorticotropic hormone) from the anterior pituitary gland. ACTH enters the systemic circulation and acts on the adrenal cortex to promote synthesis and release of glucocorticoid hormone (the major endogenous glucocorticoid being Cortisol in humans and corticosterone in rodents). The glucocorticoids exert a broad spectrum of effects, the main purpose of which is to mobilise energy sources for successful responsiveness and eventual adaptation to the stressor.

Abnormally elevated HPA axis activity in man is associated with the development of a variety of psychiatric disturbances, some of which are stress-related in aetiology. Elevated Cortisol levels, which are indicative of HPA axis hyperactivity and loss of normal negative feedback regulatory processes, are a common finding in affective disorders and various other psychiatric disturbances, and are widely utilised as a diagnostic tool (Holsboer et al., Biol. Psych., 1986, 21 , 601-61 1 ). It is generally considered that dysregulation of the HPA axis is a relection of enhanced vulnerability and poor adaptation to chronic stress and that chronic stress therefore plays a major role in the development of affective illness (Sperry and Carlson, DSM-IV diagnosis to treatment, 2^nd Edition, Taylor & Francis, 1996). This central concept is supported by experimental evidence utilising animal models of chronic stress, where abherent HPA function closely resembles that seen in clinical settings (De Goeij et al., Neuroendocrinology, 1991 , 53, 150-159; Plotsky and Meaney, MoI. Brain Res., 1993, 18, 195-200).

The major secretagogues for ACTH in humans and rats are CRH (corticotropin releasing hormone) and AVP (arginine vasopressin). Within the HPA axis these pepide hormones are synthesised by the parvocellular neurones of the paraventricular nucleus (PVN) of the hypothalamus. The axons of these neurones project to the external zone of the median eminence, from where the hormone products enter the hypophysial portal system to bathe the corticotrope cells that manufacture ACTH. CRH and AVP act synergistically at the corticotrope to regulate ACTH secretion in both rats (Rivier and Vale, Nature, 1983, 305, 325-327) and in man (De Bold et ai, J. Clin. Invest., 1984, 73, 533-538). The actions of AVP at the pituitary cortocotrope are mediated by the vasopressin V₃ (or 5 Vi_b) receptor, which is known and has been cloned (human receptor: Sugimoto et al., J. Biol. Chem., 1994, 269, 27088-27092). A report of clinical studies in depressed patients in which blunted ACTH responses to CRH could be restored by concomitant administration of desmopressin (dDAVP, an AVP agonist with V₃ affinity) confirms the involvement of the V₃ receptor in depression (Scott and Dinan, Life Sciences, 1998, 62,

10 1985-1988). A study in rodents with non-selective peptide V₃ antagonists indicates that the V₃ receptor does play a functional role in control of pituitary ACTH release (Bernardini et al., Neuroendocrinology, 1994, 60, 503-508). Vasopressin antagonists are thus utilised to modulate and normalise pituitary ACTH release and subsequent HPA axis dysfunction in CNS disorders which are characterised by abnormal HPA axis negative feedback

15 mechanisms.

In addition to the V₃ receptor, vasopressin also activates peripheral receptors, i.e., the V_1a receptor, predominantly found on liver and vascular tissue and the V₂ receptor, predominantly found on kidney tissue. Interaction at these receptors mediate the pressor 20 and antidiuretic actions of AVP.

Whilst there are several non-peptide low-molecular weight antagonists known which are selective for the V_1a or the V₂ receptor (for a recent review see Freidinger and Pettibone, Medicinal Research Reviews, 1997, 17, 1-16), there are only a small number of non- 25 peptide ligands known with selectivity for the V₃ receptor (see for example, WO 01/55130 and WO 04/009585). There exists therefore a need for further non-peptide V₃ selective antagonists which are both safe and effective.

In a first aspect, the present invention provides a 2-(1-oxo-1 /-/-isoquinolin-2-yl)acetamide 30 derivative of formula I formula I wherein

R¹ is Ci-₆alkyl, C₃.₆cycloalkyl, C₃-₆cycloalkylCi-₂alkyl, C₂-₆alkenyl or C₂-₆alkynyl, said Ci- ealkyl, C₃.₆cycloalkyl and C₃.₆cycloalkylCi-₂alkyl being optionally substituted with one or more halogens;

R² is C₆-ioaryl optionally substituted with one to three substituents selected from halogen, hydroxy, cyano, Ci_-6alkyl, C₃-₆cycloalkyl, Ci_₆alkyloxy and C₃-₆cycloalkyloxy, said Ci- ₆alkyl, C₃.₆ cycloalkyl, Ci_₆ alkyloxy and C₃.₆cycloalkyloxy being optionally substituted with one or more halogens or R² is a 5-10 membered heteroaryl ring system comprising a heteroatom selected from N, O, S and optionally substituted with a substituent selected from methyl, Ci_₆alkyloxy and halogen;

R³ is an optional substituent selected from Ci_₆alkyl, Ci_₆alkyloxy and halogen, said Ci- ₆alky and Ci-ealkyloxy being optionally substituted with one or more halogens; R⁴ is a group located at the 6- or 7- position of the oxoisoquinoline ring and is selected from

each R⁵ is independently H or Ci_₆alkyl or one of R⁵ when joined together with one of R⁶ or R⁷ forms a 4-7 membered heterocyclic ring; R⁶ and R⁷ are independently H, Ci_₆alkyl, C₃.₆cycloalkyl, C₃-₆cycloalkylCi-₂alkyl, C₆-io aryl or C₆-ioarylCi-₂alkyl; or R⁶ and R⁷ together with the nitrogen to which they are bonded form a 4 to 8 membered saturated or unsaturated heterocyclic ring optionally comprising a further heteroatomic moiety selected from O, S and NR¹⁰, said heterocyclic ring being optionally substituted with one or two substituents selected from halogen, hydroxyl, Ci_₆alkyl, Ci_₆alkyloxy, cyano and COOR¹¹ and said heterocyclic ring being optionally fused at two adjacent carbon atoms to a phenyl ring; or one of R⁶ and R⁷ when joined together with one of R⁵ forms a 4-7 membered heterocyclic ring; or one of R⁶ and R⁷ when joined together with one of R⁸ forms a 5-6 membered heterocyclic ring;

R⁸ is one or two substituents selected from H, Ci_₆alkyl, Ci_₆alkyloxy and halogen or one of R⁸ when joined together with one of R⁶ and R⁷ forms a 5-6 membered heterocyclic ring; or one of R⁸ when joined together with R⁹ forms a 5-6 membered ring

R⁹ is H or Ci-₆alkyl or R⁹ when joined together with one of R⁸ forms a 5-6 membered ring;

R¹⁰ is H, Ci_₆alkyl or Ci_₆acyl;

R¹¹ is H or d_₆alkyl; m is 2-4; n is 1-3;

X iS CH₂, O, S, SO₂ Or NR¹²;

R¹² is H, Ci-₆alkyl, Ci_₆acyl or C₆-ioarylCi_₂alkyl group, said C₆-ioarylCi_₂alkyl group being optionally substituted with methyl or methoxy;

Y is CH₂, (CH₂)₂ or (CH₂)₃; Q, T, V and W are C or N with the proviso that one of Q, T, V and W is N and the others are C;

Q', T and V are selected from C, O, N and S with the proviso that one of Q', T and V is

O, N, or S and the others are C; or a pharmaceutically acceptable salt or solvate thereof.

The term Ci_₆ alkyl, as used herein, represents a branched or unbranched alkyl group having 1-6 carbon atoms. Examples of such groups are methyl, ethyl, isopropyl, tertiary- butyl, pentyl and hexyl. The term C₂-₆ alkenyl, as used herein, represents a branched or unbranched alkenyl group having 2-6 carbon atoms and at least one double bond. Examples of such groups are ethenyl and 3-methylbutynyl.

The term C₂-₆ alkynyl, as used herein, represents a branched or unbranched alkynyl group having 2-6 carbon atoms and at least one triple bond. Examples of such groups are ethynyl and 3-methylbutynyl.

The term C₃.₆ cycloalkyl, as used herein, represents a branched or unbranched cyclic alkyl group having 3-6 carbon atoms. Examples of such groups are cyclopropyl, cyclopentyl and 2-methylcyclopentyl.

The term C₃-₆cycloalkylCi-₂alkyl, as used herein, represents a Ci_₂ alkyl group which is substituted with a C₃-₆cycloalkyl group. Examples of such groups are cyclopropylmethyl and 2-cyclobutylethyl.

The term Ci_₆ alkyloxy, as used herein, represents a branched or unbranched alkyloxy group having 1-6 carbon atoms. Examples of such groups are methoxy, ethoxy, isopropyloxy and tertiary-butyloxy.

The term C₃.₆ cycloalkyloxy, as used herein, represents a branched or unbranched cyclic alkyloxy group having 3-6 carbon atoms. Examples of such groups are cyclopropyloxy, cyclopentyloxy and 2-methylcyclopentyloxy. Similarly, the term C₄.₆ cycloalkyloxy represents a branched or unbranched cyclic alkyloxy group having 4-6 carbon atoms.

The term Ci_₆ acyl, as used herein, represents an acyl group derived from a carboxylic acid having 1-6 carbon atoms. The acyl group can comprise a hydrocarbon which may be branched, unbranched, saturated or unsaturated. Examples of such groups include formyl, acetyl, propionyl, acryloyl and pivaloyl. Also included within the definition of Ci_₆ acyl are groups derived from dicarboxylic acids like groups derived from malonic acid.

The term C₆-io aryl, as used herein, represents an aromatic group having 6-10 carbon atoms. Examples of such groups include phenyl and naphthyl. The term C₆-ioarylCi-₂alkyl, as used herein, represents a Ci_₂ alkyl group which is substituted with a C₆-io aryl group. Examples of such groups include benzyl and phenethyl.

The term halogen, as used herein, represents a fluorine, chlorine, bromine or iodine.

The term 5-10 membered heteroaryl ring system comprising a heteroatom selected from N, O and S, as used herein, represents a monocyclic or fused bicyclic 5-10 membered heteroaryl ring system comprising a heteroatom selected from N, O and S. Examples of such groups include furanyl, thienyl, pyrrolyl, pyridinyl, indolyl, benzthienyl and quinolinyl.

Examples of 4 to 8 membered saturated or unsaturated heterocyclic rings formed by R⁶ and R⁷ together with the nitrogen to which they are bonded and optionally comprising a further heteroatomic moiety selected from O, S and NR¹⁰ wherein R⁶, R⁷ and R¹⁰ have the previously defined meanings, as used herein, include piperidine, homopiperidine, morpholine, thiomorpholine, 4-methylpiperazine, tetrahydropyridine and 4- methylhomopiperazine.

In one embodiment of the present invention R¹ is C-i-ealkyl, C₃-₆Cycloalkyl or C₃-₆ cycloalkylCi-_∑alkyl. In a further embodiment R¹ is C₃.₄alkyl, C₃.₄cycloalkyl or C₃.₄ cycloalkylCi-_∑alkyl. In a further embodiment R¹ is isopropyl, isobutyl, tertiary-butyl or cyclopropylmethyl.

In another embodiment R² is C₆-ioaryl, optionally substituted with one to three substituents selected from halogen, hydroxy, cyano, C_1-6alkyl, C₃-₆cycloalkyl, Ci_₆alkyloxy and C₃.₆ cycloalkyloxy, said C_1-6alkyl, C₃.₆ cycloalkyl, C_1-6 alkyloxy and C₃.₆cycloalkyloxy being optionally substituted with one or more halogens. In a further embodiment R² is a phenyl ring. In a further embodiment R² is a 3-substituted phenyl ring. In a further embodiment R² is a 3-substituted phenyl ring substituted with one to three substituents selected from chloro, fluoro, C^alkyl, trifluoromethyl, C^alkyloxy, C_1-4 cycloalkyloxy and trifluoromethoxy. In a further embodiment R² is a substituted phenyl ring selected from 3- chlorophenyl, 3-fluorophenyl, 3-methoxyphenyl, 3-trifluoromethoxyphenyl, 3-chloro-4- fluorophenyl and 4-fluoro-3-methoxyphenyl. In another embodiment R² is a 5-10 membered heteroaryl ring system comprising a heteroatom selected from N, O and S and optionally substituted with a substituent selected from methyl, Ci_₆alkyloxy and halogen. In a further embodiment R² is a 2-thienyl, 3-thienyl, 2-pyridyl or 6-indolyl optionally substituted with chloro, methyl or methoxy.

In another embodiment, R⁴ is the group

wherein X, m and R⁵ - R⁷ have the meanings as defined previously. In a further embodiment R⁵ is H or methyl and m is 3. In a further embodiment R⁴ is a group selected from

wherein R⁶ and R⁷ have the meanings as defined previously.

In another embodiment, R⁴ is the group

wherein X, Y, R⁶ and R⁷ have the meanings as defined previously. In a further embodiment X is O or CH₂ and Y is CH₂.

In another embodiment, R⁴ is the group

wherein n and R⁵ - R⁷ have the meanings as defined previously. In a further embodiment R⁵ is methyl and n is 2.

In another embodiment R⁴ is the group

wherein R⁶ to R⁹ have the meanings as defined previously. In a further embodiment R⁸ and R⁹ are H.

In another embodiment, R⁴ is the group

wherein Q', T, V and R⁶ - R⁹ have the meanings as defined previously. In a further embodiment R⁸ and R⁹ are both H.

In another embodiment, R⁴ is the group

wherein Q, T, V, W and R⁶ - R⁹ have the meanings as defined previously. In a further embodiment R⁸ and R⁹ are both H.

In another embodiment, R⁴ is a group selected from wherein R⁶ and R⁷ have the meanings as defined previously.

In another embodiment R⁶ and R⁷ are independently H, Ci_₆alkyl, C₃.₆cycloalkyl, C₃. ecycloalkylCi-_∑alkyl, C_6-io aryl or C₆-ioarylCi.₂alkyl. In a further embodiment R⁶ and R⁷ are independently H or Ci_₄alkyl.

In another embodiment, R⁶ and R⁷ together with the nitrogen to which they are bound form a 4 to 7 membered heterocyclic ring optionally comprising a further heteroatomic moiety selected from O, S or NR¹⁰, said heterocyclic ring being optionally substituted with a hydroxyl substituent, wherein R¹⁰ has the previously defined meaning. In a further embodiment R⁶ and R⁷ together with the nitrogen to which they are bound form a heterocyclic ring selected from pyrrolidine, piperidine, 3-hydroxypiperidine and morpholine.

In a further embodiment is a 2-(1-oxo-1 /-/-isoquinolin-2-yl)acetamide selected from:

Λ/-terf-Butyl-2-[3-(4-fluoro-3-methoxyphenyl)-1-oxo-7-(3-pyrrolidin-1-ylpropoxy)-1 /-/- isoquinolin-2-yl]acetamide;

2-[3-(3-Chlorophenyl)-7-((S)-2-methyl-3-pyrrolidin-1 -ylpropoxy)-1 -oxo-1 /-/-isoquinolin-2-yl]- Λ/-isopropylacetamide and

Λ/-terf-Butyl-2-[3-(3-chloro-4-fluorophenyl)-1-oxo-7-(3-pyrrolidin-1-ylpropoxy)-1 /-/- isoquinolin-2-yl]acetamide or a pharmaceutically acceptable salt or solvate thereof.

The compounds of the present invention are prepared by methods well known in the art of organic chemistry. See, for example, J. March, 'Advanced Organic Chemistry' 4^th Edition, John Wiley and Sons. During synthetic sequences it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This is achieved by means of conventional protecting groups, such as those described in T. W. Greene and P. G. M. Wuts 'Protective Groups in Organic Synthesis' 2^nd Edition, John Wiley and Sons, 1991. The protective groups are optionally removed at a convenient subsequent stage using methods well known in the art.

Compounds of formula I wherein R⁴ is the group

and X is O (shown as 10 below) can be prepared by the general five stage synthetic sequence shown in Scheme 1. Firstly a suitably functionalised 2-halobenzoic acid ester of formula 2, is reacted with a suitably functionalised styrene of formula 3 in the presence of a suitable Pd(II) catalyst (for example palladium diacetate), a triarylphosphine ligand (for example tri(o-tolyl)phosphine) and a tertiary amine base (for example triethylamine) in a polar aprotic solvent (for example acetonitrile) to give the coupled product 4. P represents a suitable protecting group, for example methyl. The 2-halobenzoic acids 2 and styrenes 3 are either commercially available or they can readily be prepared by procedures well known in the art. The carboxylic acid ester 4 is then hydrolysed to the carboxylic acid 5 using either acid or base in a suitable solvent such as ethanol. The carboxylic acid intermediate 5 is subsequently cyclised to the isocoumarin 6 using a palladium(ll) catalyst, for example, bis(acetonitrile)dichloropalladium(ll) and an oxidant , for example, p-benzoquinone, in an inert solvent, for example, tetrahydrofuran. The isocoumarin 6 thus obtained is heated together with a glycine amide 7 to provide the isoquinolinone 8 which is subsequently deprotected. The free hydroxyl group is then functionalised with an alcohol of formula 9 utilizing, for example, standard Mitsunobu reaction conditions, Ae., in the presence of triphenylphosphine and diethylazodicarboxylate or DIAC to provide the desired product 10. Alcohols of formula 9 are either commercially available or they can readily be prepared by procedures well known in the art.

hydrolysis

2. deprotection

Scheme 1

The desired products 10 can also be prepared by alkylation of the hydroxy isoquinolinone 8 in the presence of a suitable base with a compound of formula 11 wherein L is a suitable leaving group. A suitable base would be, for example, a metal carbonate such as potassium carbonate or cesium carbonate. Suitable leaving groups would be, for example, a mesylate or tosylate group or a halide (Scheme 2). Compounds of formula 11 are either commercially available or they can readily be prepared by procedures well known in the art.

Scheme 2

The desired products 10 can also alternatively be prepared by a two-step procedure involving first, a base-mediated alkylation of a hydroxy isoquinolinone 8, with a suitable dihaloalkane, such as 3-bromo-1-chloropropane, followed by nucleophilic displacement with an amine of formula HNR⁶R⁷ (Scheme 3). Dihaloalkanes and amines of formula HNR⁶R⁷ are either commercially available or they can readily be prepared by procedures well known in the art.

Scheme 3

A related three-step procedure by which the desired products 10 can also be prepared involves firstly alkylation of the aforementioned hydroxy isoquinolinone 8 with a suitable haloalkanol, such as 3-bromopropan-1-ol, followed by conversion of the hydroxyl group to a suitable leaving group, such as halide or mesylate, utilizing various methods known to one skilled in the art, and finally, displacement of said leaving group with an amine of formula HNR⁶R⁷ to provide the desired product 10 (Scheme 4). The 2-haloalkanols are either commercially available or they can readily be prepared by procedures well known in the art.

L= OMs, Br etc.

Scheme 4

Compounds of formula I wherein R is a group having the formula

and X is NR¹² (13) can be prepared by reaction of intermediates of formula I wherein R⁴ is a suitably reactive group such as a triflate, with diamines of formula 12 in the presence of a suitable catalyst system, such as Pd₂(dba)₃ and BINAP, under conditions well known in the art (Scheme 5). Intermediates of formula I wherein R⁴ is triflate can readily be prepared from the corresponding alcohols 8 using procedures well known in the art, for example by treatment of alcohols 8 with trifluoromethanesulfonic anhydride and pyridine. Diamines of formula 12 are either commercially available or they can readily be prepared by procedures well known in the art.

Compounds of formula I wherein R is

and X is O or NR¹² can be prepared using analogous procedures and/or reaction sequences to those described above in Schemes 1-5.

Compounds of formula I, wherein R is the group

(16) can be prepared by first reacting an intermediate of formula I wherein R⁴ is a group such as triflate with a terminal alkene of formula 14 (wherein L is a displaceable group such as halide or a group such as hydroxyl which can subsequently be converted to a displaceable group such as halide, mesylate, or tosylate) in the presence of a base such as triethylamine, a suitable catalyst such as Pd(OAc)₂, and a triarylphosphine ligand such as tri(o-tolyl)phosphine to give the intermediate 15. The amine 16 is then formed from the alkene 15 by displacement of leaving group L with an aliphatic amine of formula HNR⁶R⁷. The corresponding saturated derivative 17 can be obtained by hydrogenation of the unsaturated amine 16 in the presence of, for example, a palladium on carbon catalyst (Scheme 6). Alkenes of formula 14 are either commercially available or they can readily be prepared by procedures well known in the art.

R4 = OTf etc.

Scheme 6

Compounds of formula I, wherein R⁴ is the group

(23) can be prepared by coupling of an intermediate of formula I wherein R is a suitably reactive group such as triflate, with a boronic acid or ester of formula 18 or 19 (A = B(OH)₂ or B(OR)₂)

in the presence of a suitable catalyst such as Pd(PPh₃)₄ followed by conversion to the desired amine by a variety of methods familiar to one skilled in the art. For example, adduct 21 can be obtained upon reaction of intermediate of formula I, wherein R⁴ is triflate with the boronate 20 in the presence of Pd(PPh₃)₄. This can then be converted to intermediate 22 in which the hydroxyl group has been converted to a leaving group, such as halide or mesylate. Compound 22 can then in turn be treated with an amine of formula HNR⁶R⁷ to afford the desired product 23 (Scheme 7). Compounds of formula 18, 19, 20 are either commercially available or they can readily be prepared by procedures well known in the art.

22

Scheme 7

Alternatively, adduct 25 can be obtained by reaction of intermediate of formula I with boronate 24. This can then be converted to the desired amine product 23 upon treatment with HNR⁶R⁷ in the presence of a suitable reducing agent such as sodium triacetoxyborohydride or sodium cyanoborohydride (Scheme 8). Boronates 24 are either commercially available or they can readily be prepared by procedures well known in the art.

23

Scheme 8

A further method by which the desired products (23) can be obtained involves coupling of an intermediate boronate (26), prepared via an intermediate halide or triflate of formula I (R⁴ = halide or triflate) by reaction of said halide or triflate with bis(pinacolato)diboron in the presence of a suitable catalyst such as PdCI₂(dppf) and a base such as KOAc (Scheme 9). This can then be coupled with an aryl halide or triflate of formula 27 or 28 (A = halide or triflate) using analogous procedures to those shown in Schemes 7 and 8 to provide the adducts 29 and 30 which are then converted to the product 23.

26

R⁴ = OTf, etc

Scheme 9

Compounds of formula I, wherein R⁴ is a group selected from

can prepared using the same general procedures and/or reaction sequences described above in Schemes 7-9.

It will be readily appreciated by one skilled in the art that the isoquinolinones of general formula I can be prepared using the general procedures and/or reaction sequences described above in any suitable order. For example, whereas the processes detailed above describe introduction of the R⁴ groups later in the syntheses utilizing preformed isoquinolinone intermediates, it will be recognized that, in some cases, the R⁴ groups can be introduced before the formation of the isoquinolinone ring system.

Hence compounds of formula I wherein R⁴ is a group having the formula and X is O can be prepared in 5 stages from phenol 31 as shown in Scheme 10. The phenol 31 is either commercially available or prepared using procedures well known in the art of organic chemistry. The phenol can be alkylated using analogous procedures to those shown above in Schemes 1-4 to provide the amino ether 32. This is then coupled with the styrene 3 in an analogous manner to that indicated in Scheme 1 to provide the coupled product 33. Upon treatment with either aqueous acid or base in a suitable solvent, for example, using hydrochloric acid in ethanol, the ester group can then be hydrolysed to yield the benzoic acid intermediate 34. This is subsequently cyclised to the isocoumarin 35 using a palladium(ll) catalyst, for example, ό/s(acetonitrile)dichloropalladium(ll) and an oxidant , for example, p-benzoquinone, in an inert solvent, for example, tetrahydrofuran. The isocoumarin 35 is subsequently reacted with the glycine amide 7, using analogous procedures to those indicated previously (see Scheme 1 ) to yield the isoquinolinone 10.

3

Pd(Il)₁ Ar₃P

Scheme 10

Compounds of formula I wherein R is a group having the formula

and X is SO₂ can be prepared by oxidation of the corresponding sulphides using, for example, m-chloroperoxybenzoic acid in dichloromethane. The present invention also includes within its scope all stereoisomeric forms of 2-(1-oxo- 1 /-/-isoquinolin-2-yl)acetamide derivatives resulting, for example, because of config u rational or geometrical isomerism. Such stereoisomeric forms are enantiomers, diastereoisomers, cis and trans isomers etc. For example, in the case where R¹ is 2- methylbutyl the compound exists as a pair of enantiomers. In the case where R⁴ comprises an alkene fragment, both (Z) and (E) stereoisomeric forms of the compound are possible. In the case of the individual enantiomers of compounds of formula I or salts or solvates thereof, the present invention includes the aforementioned stereoisomers substantially free, Ae., associated with less than 5%, preferably less than 2% and in particular less than 1 % of the other enantiomer. Mixtures of stereoisomers in any proportion, for example a racemic mixture comprising substantially equal amounts of two enantiomers are also included within the scope of the present invention.

For chiral compounds, methods for asymmetric synthesis whereby the pure stereoisomers are obtained are well known in the art, e.g., synthesis with chiral induction, synthesis starting from chiral intermediates, enantioselective enzymatic conversions, separation of stereoisomers using chromatography on chiral media. Such methods are described in

Chirality In Industry (edited by A.N. Collins, G.N. Sheldrake and J. Crosby, 1992; John

Wiley). Likewise methods for synthesis of geometrical isomers are also well known in the art.

The present invention also includes within its scope all isotopically labelled forms of the 2- (1-OXO-1 /-/-isoquinolin-2-yl)acetamide derivatives of the invention. For example, compounds isotopically labelled with ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹³¹I, ¹²⁵I, ¹²³I and ¹⁸F. The labelled compounds are useful as diagnostic tools, radio tracers, or monitoring agents in various diagnostic methods and for in vivo receptor imaging.

The 2-(1-oxo-1 /-/-isoquinolin-2-yl)acetamide derivatives of the present invention, in the form as a free base, are isolated from reaction mixtures as pharmaceutically acceptable salts. These salts are also obtained by treatment of said free base with an organic or inorganic acid, for example, hydrogen chloride, hydrogen bromide, hydrogen iodide, sulfuric acid, phosphoric acid, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, maleic acid, malonic acid, methanesulfonic acid, fumaric acid, succinic acid, tartaric acid, citric acid, benzoic acid and ascorbic acid. The 2-(1 -oxo-1 /-/-isoquinolin-2-yl)acetamide derivatives of the present invention exist in both solvated and unsolvated forms, including hydrated forms. These forms are also encompassed within the scope of the present invention.

The 2-(1 -oxo-1 /-/-isoquinolin-2-yl)acetamide derivatives of the present invention also exist as amorphous forms. Multiple crystalline forms are also possible. All these physical forms are included within the scope of the present invention.

In a further aspect, the 2-(1-oxo-1 /-/-isoquinolin-2-yl)acetamide derivatives of the present invention and their pharmaceutically acceptable salts and solvates are useful in therapy.

As such the compounds of the present invention are useful for the manufacture of a medicament for the treatment or prevention of diseases influenced by modulation of the activity of the HPA axis. In particular the compounds are useful for the manufacture of a medicament for the treatment of schizophrenia, anxiety, hot flushes, addiction, anorexia nervosa, stress-related disorders and Alzheimer's dementia.

In a further aspect, the 2-(1-oxo-1 /-/-isoquinolin-2-yl)acetamide derivatives of the present invention are useful for the manufacture of a medicament for the treatment or prevention of depression. Depression states in the treatment of which the compounds of the present invention and their pharmaceutically acceptable salts and solvates are particularly useful are those classified as mood disorders in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition- Text Revised, American Psychiatric Association, Washington D. C. (2000), including mood episodes, depressive disorders, bipolar disorders and other mood disorders.

The present invention further includes a method for the treatment of a mammal, including a human, suffering from or liable to suffer from depression or any of the aforementioned disorders, which comprises administering an effective amount of a 2-( 1 -oxo-1 H- isoquinolin-2-yl)acetamide derivative of the present invention or a pharmaceutically acceptable salt or solvate thereof.

The amount of a 2-(1 -oxo-1 /-/-isoquinolin-2-yl)acetamide derivative of the present invention or a pharmaceutically acceptable salt or solvate thereof, also referred to herein as the active ingredient, which is required to achieve a therapeutic effect will, of course, vary with the particular compound, the route of administration, the age and condition of the recipient, and the particular disorder or disease being treated.

A suitable daily dose for any of the above mentioned disorders will be in the range of 0.001 to 50 mg per kilogram body weight of the recipient (e.g. a human) per day, preferably in the range of 0.01 to 20 mg per kilogram body weight per day. The desired dose may be presented as multiple sub-doses administered at appropriate intervals throughout the day.

Whilst it is possible for the active ingredient to be administered alone, it is preferable to present it as a pharmaceutical formulation. The present invention therefore also provides a pharmaceutical composition comprising a 2-(1-oxo-1 /-/-isoquinolin-2-yl)acetamide derivative according to the present invention in admixture with one or more pharmaceutically acceptable auxiliaries, such as the ones described in Gennaro et. ai, Remmington: The Science and Practice of Pharmacy, 20^th Edition, Lippincott, Williams and Wilkins, 2000; see especially part 5: pharmaceutical manufacturing. Suitable auxiliaries are described e.g., in the Handbook of Pharmaceutical Excipients, 2^nd Edition; Editors A. Wade and P.J.Weller, American Pharmaceutical Association, Washington, The Pharmaceutical Press, London, 1994. Compositions include those suitable for oral, nasal, topical (including buccal, sublingual and transdermal), parenteral (including subcutaneous, intravenous and intramuscular) or rectal administration.

The mixtures of a 2-(1-oxo-1 /-/-isoquinolin-2-yl)acetamide derivative according to the present invention and one or more pharmaceutically acceptable auxiliary or auxiliaries may be compressed into solid dosage units, such as tablets, or be processed into capsules or suppositories. By means of pharmaceutically suitable liquids the 2-(1-oxo-1 A7- isoquinolin-2-yl)acetamide derivatives can also be applied as an injection preparation in the form of a solution, suspension, emulsion, or as a spray, e.g., a nasal or buccal spray. For making dosage units e.g., tablets, the use of conventional additives such as fillers, colorants, polymeric binders and the like is contemplated. In general, any pharmaceutically acceptable additive can be used. The 2-(1-oxo-1 /-/-isoquinolin-2- yl)acetamide derivatives of the invention are also suitable for use in an implant, a patch, a gel or any other preparation for immediate and/or sustained release. Suitable fillers with which the pharmaceutical compositions can be prepared and administered include lactose, starch, cellulose and derivatives thereof, and the like, or mixtures thereof used in suitable amounts.

The following Examples further illustrate the compounds of the present invention and methods for their synthesis. In the following section, there is described the synthesis of precursors and common intermediates for compounds of the present invention.

Procedure I INTERMEDIATE 1.1 : 2-Amino-Λ/-isopropylacetamide

H

'^N- - ^

NH,

a) (IsopropylcarbamoylmethvDcarbamic acid benzyl ester

To a solution of Λ/-Cbz-glycine (20.9 g, 100 mmol) in THF (400 mL) at 0 ⁰C was added N- methylmorpholine (NMM) (12.1 mL, 1 10 mmol) and /-butylchloroformate (13 mL, 100 mmol). The resultant mixture was stirred at 0 ⁰C for 2 min and then /-propylamine (9.4 mL, 1 10 mmol) was added. The reaction mixture was warmed to room temperature and stirred at this temperature for 16 h. The mixture was filtered through a pad of Celite and concentrated in vacuo. The crude residue was dissolved in ethyl acetate (500 mL) and washed with 1 N HCI (aq.) (1 x 100 mL), sat. NaHCO₃ (aq.) (1 x 100 mL) and brine (1 x 100 mL). The organic layer was dried (MgSO₄), filtered and concentrated in vacuo to afford (isopropylcarbamoylmethyljcarbamic acid benzyl ester (24.5 g, 98 mmol, 98%) as a white solid which was used without further purification in the next reaction. Data for (isopropylcarbamoylmethyl)carbamic acid benzyl ester. ¹H NMR (300 MHz, CDCI₃): δ 7.37 (m, 5H), 5.78 (br s, 1 H), 5.41 (br s, 1 H), 5.15 (s, 2H), 4.07 (septet, 1 H), 3.82 (d, 2H), 1.15 (d, 6H) ppm.

b) 2-Amino-Λ/-isopropylacetamide 10% Pd/C (425 mg) was added to a solution of (isopropylcarbamoylmethyOcarbamic acid benzyl ester (10 g, 40 mmol) in EtOH (200 ml_) and shaken under 50 p.s.i. H₂ (g) in a Parr shaker for 16 h. The reaction mixture was filtered through a pad of Celite and the solvent removed in vacuo. This afforded 2-amino-N-isopropylacetamide (INTERMEDIATE 1.1) as a clear, colourless oil (5.1 g, 40 mmol, 100%).

Data for 2-amino-N-isopropylacetamide (INTERMEDIATE 1.1): ¹H NMR (300 MHz, CDCI₃): δ 7.05 (br s, 1 H), 4.1 1 (septet, 1 H), 3.33 (s, 2H), 1.48 (br s, 2H, amine NH₂), 1.15 (d, 6H) ppm.

Similarly prepared was:

INTERMEDIATE I.2: 2-Amino-Λ/-ferf-butylacetamide

Procedure Il

INTERMEDIATE 11.1 : 1-Fluoro-2-methoxy-4-vinylbenzene

To a stirred suspension of methyltriphenylphosphonium bromide (68.20 g, 0.191 mol) in anhydrous THF (400 ml_) cooled to -40 ⁰C was added n-butyllithium (2.5 M in hexanes, 71.2 ml_, 0.178 mol) via syringe over 15 min, at which point the characteristic yellow color of the phosphorus ylide persisted. The reaction mixture was warmed to -10 ⁰C over 1 h to complete the reaction. The mixture was subsequently cooled to -30 ⁰C and a solution of 4- fluoro-3-methoxybenzaldehyde (10.00 g, 63.64 mmol) in anhydrous THF (40 ml_) was added via a cannula over 10 min. The resultant mixture was warmed to ambient temperature over 16 h. The reaction was quenched by gradual addition of water (200 ml_) and the aqueous extracted with diethyl ether (3 x 200 ml_). The combined organic layers were washed with water (2 x 200 ml_), brine (200 ml_), dried (MgSO₄) and concentrated under reduced pressure to give 1-fluoro-2-methoxy-4-vinylbenzene (INTERMEDIATE 11.1) (8.69 g, 57.1 mmol, 90 %) as a yellow oil.

Data for 1-fluoro-2-methoxy-4-vinylbenzene (INTERMEDIATE 11.1): ¹H NMR (300 MHz, CDCI₃): δ 7.05-6.90 (m, 3H), 6.67 (dd, 1 H), 5.67 (d, 1 H), 5.24 (d, 1 H), 3.92 (s, 3H) ppm.

Similarly prepared were:

INTERMEDIATE II.2: 2-methoxy-6-vinylpyridine (from 6-methoxypicolinaldehyde) INTERMEDIATE 11.3: 1-chloro-2-fluoro-5-vinylbenzene (from 3-chloro-4- fluorobenzaldehyde)

Procedure III: Method A INTERMEDIATE 111.1 : Λ/-terf-Butyl-2-r3-(4-fluoro-3-methoxyphenyl)-7-hvdroxy-1-oxo-1 A7- isoαuinolin-2-yliacetamide

a) 2-lodo-5-(4-methoxybenzyloxy)benzoic acid 4-methoxybenzyl ester

To a stirred solution of 2-iodo-5-hydroxybenzoic acid (prepared according to the method described in J. Am. Chem. Soc, 1984, 106, 2651 ) (27.15 g, 103 mmol) in anhydrous acetonitrile (400 ml_) was added cesium carbonate (73.80 g, 227 mmol) and A- methoxybenzyl chloride (33.5 ml_, 247 mmol). The resulting solid mass was broken up and the mixture heated at 65 ⁰C for 15 h. The reaction mixture was poured into sat. NaHCO₃ (aq.) (400 ml_) and the resultant mixture extracted with ethyl acetate (3 x 300 ml_). The combined organic extracts were washed with brine (300 ml_), dried (MgSO₄) and concentrated in vacuo. The crude product was purified by chromatography on silica gel with a gradient of ethyl acetate:hexanes (1 :9, v/v) to ethyl acetate:hexanes (1 :3, v/v) as eluent to afford 2-iodo-5-(4-methoxybenzyloxy)benzoic acid 4-methoxybenzyl ester (15.39 g, 30.52 mmol, 30%).

Data for 2-iodo-5-(4-methoxybenzyloxy)benzoic acid 4-methoxybenzyl ester: ¹H NMR (400 MHz, (CDs)₂SO): δ 7.81 (d, 1 H), 7.39 (d, 2H), 7.32 (d, 2H), 7.27 (d, 1 H), 6.95-6.84 (m, 5H), 5.21 (s, 2H), 5.01 (s, 2H), 3.73 (s, 3H), 3.71 (s, 3H) ppm. b) (E)-2-[2-(4-Fluoro-3-methoxyphenyl)vinyl1-5-(4-methoxybenzyloxy)benzoic acid A- methoxybenzyl ester

To a stirred solution of 1-fluoro-2-methoxy-4-vinylbenzene (INTERMEDIATE 1.1 ) (4.49 g, 29.53 mmol) and 2-iodo-5-(4-methoxybenzyloxy)benzoic acid 4-methoxybenzyl ester

(14.89 g, 29.53 mmol) in anhydrous acetonitrile (75 ml_) was added triethylamine (8.2 ml_,

59.06 mmol) and tri(o-tolyl)phosphine (1.17 g, 3.84 mmol). The mixture was sparged for 5 min with argon, and palladium(ll) acetate (662 mg, 2.95 mmol) was added. The mixture was heated at reflux for 13 h and concentrated to give the crude product (E)-2-[2-(4- fluoro-3-methoxyphenyl)vinyl]-5-(4-methoxybenzyloxy)benzoic acid 4-methoxybenzyl ester as a dark brown residue, which was used without further purification.

c) (E)-2-[2-(4-Fluoro-3-methoxyphenyl)vinyl1-5-(4-methoxybenzyloxy)benzoic acid

To a stirred suspension of crude (ΕJ-2-[2-(4-fluoro-3-methoxyphenyl)vinyl]-5-(4- methoxybenzyloxy)benzoic acid 4-methoxybenzyl ester in MeOH:THF:H₂O (3:1 :1 v/v, 150 ml_) was added lithium hydroxide monohydrate (4.95 g, 1 18 mmol). The resultant suspension was stirred for 15 h at ambient temperature, then concentrated in vacuo. The residue was taken up in H₂O (500 ml_), and the solution was extracted with ethyl acetate (2 x 200 ml_). The aqueous phase was acidified to pH 2 with cone. HCI, and the mixture was extracted with ethyl acetate (3 x 200 ml_), dried (MgSO₄) and concentrated in vacuo to give (E)-2-[2-(4-fluoro-3-methoxyphenyl)vinyl]-5-(4-methoxybenzyloxy)benzoic acid (8.75 g, 21.4 mmol, 73 % from 2-iodo-5-(4-methoxybenzyloxy)benzoic acid A- methoxybenzyl ester as a light brown powder.

d) 3-(4-Fluoro-3-methoxyphenyl)-7-(4-methoxybenzyloxy)isochromen-1-one

A solution of (E)-2-[2-(4-fluoro-3-methoxyphenyl)vinyl]-5-(4-methoxybenzyloxy)benzoic acid (600 mg, 1.47 mmol) in anhydrous THF (5 ml_) was sparged with nitrogen for 5 min, then PdCI₂(MeCN)₂ (39 mg, 0.15 mmol), p-benzoquinone (175 mg, 1.62 mmol), and molecular sieves (10 mg) were added and the mixture stirred at room temperature for 24 h. The reaction mixture was diluted with ethyl acetate and washed with 1 N NaOH (aq.).

The organic layer was washed with brine, dried (MgSO₄) and concentrated in vacuo. The crude residue was purified by chromatography on silica gel with hexanes:EtOAc (2:1 , v/v) as eluent to afford 3-(4-fluoro-3-methoxyphenyl)-7-(4-methoxybenzyloxy)isochromen-1- one (300 mg, 0.74 mmol, 50 %).

Data for 3-(4-fluoro-3-methoxyphenyl)-7-(4-methoxybenzyloxy)isochromen-1-one: ¹H NMR (400 MHz, CDCI₃): δ 7.80 (d, 1 H), 7.46-7.35 (m, 6H), 7.13 (dd, 1 H), 6.94 (d, 2H), 6.86 (s, 1 H), 5.09 (s, 2H), 3.98 (s, 3H), 3.82 (s, 3H) ppm.

e) Λ/-terf-Butyl-2-(3-(4-fluoro-3-methoxyphenyl)-7-(4-methoxybenzyloxy)-1-oxo-1 /-/- isoquinolin-2-yl)acetamide

A neat mixture of 3-(4-fluoro-3-methoxyphenyl)-7-(4-methoxybenzyloxy)isochromen-1-one (100 mg, 0.25 mmol) and 2-amino-Λ/-ferf-butyl acetamide (INTERMEDIATE I.2) (32 mg, 2.46 mmol) was heated at 120 ⁰C for 3 h. The reaction mixture was cooled and partitioned between ethyl acetate and sat. NH₄CI (aq.). The organic layer was washed with brine (1 X 20 ml_), dried (MgSO₄) and concentrated in vacuo to afford N-tert-butyl-2- (3-(4-fluoro-3-methoxyphenyl) - 7-(4-methoxybenzyloxy)- 1 -oxo- 1 H-isoquinolin-2- yl)acetamide (120 mg, 0.23 mmol, 94%) which was used in the next step without further purification.

Data f o r N-tert-butyl-2-(3-(4-fluoro-3-methoxyphenyl) - 7-(4-methoxybenzyloxy) - 1 -oxo- 1 H- isoquinolin-2-yl)acetamide: MS (ESI) m/z: 519 ([M+H]⁺).

f) Λ/-terf-Butyl-2-(3-(4-fluoro-3-methoxyphenyl)-7-hvdroxy-1-oxo-1 /-/-isoquinolin-2- vDacetamide (INTERMEDIATE 111.1 )

N-terf-Butyl-2-(3-(4-fluoro-3-methoxyphenyl)-7-(4-methoxybenzyloxy)-1-oxo-1 /-/- isoquinolin-2-yl)acetamide (120 mg, 0.231 mmol) was treated with TFA:DCM (1 :1 v/v, 5 ml_) and stirred at room temperature for 1 h. The mixture was concentrated in vacuo and the crude residue was purified by preparative HPLC giving N-tert-butyl-2-(3-(4-fluoro-3- methoxyphenyl)-7-hydroxy-1 -oxo-1 H-isoquinolin-2-yl)acetamide (INTERMEDIATE III.1) (25 mg, 0.063 mmol, 27%). Data for N-tert-butyl-2-(3-(4-fluoro-3-methoxyphenyl)-7-hydroxy-1 -oxo-1 H-isoquinolin-2- yl)acetamide (INTERMEDIATE III.1): MS (ESI) m/z: 399 ([M+H]⁺).

Similarly prepared were:

INTERMEDIATE III.2: 2-[3-(4-Fluoro-3-methoxyphenyl)-7-hydroxy-1-oxo-1 /-/-isoquinolin- 2-yl]-Λ/-isopropylacetamide (from INTERMEDIATE 11.1 & INTERMEDIATE 1.1 )

INTERMEDIATE III.3: 2-[7-Hydroxy-3-(3-methoxyphenyl)-1-oxo-1 H-isoquinolin-2-yl]-Λ/- isopropylacetamide (from INTERMEDIATE 1.1 and 3-methoxystyrene) INTERMEDIATE III.4: Λ/-ferf-Butyl-2-[7-hydroxy-3-(3-methoxyphenyl)-1 -oxo-1 H- isoquinolin-2-yl]acetamide (from INTERMEDIATE 1.2 and 3-methoxystyrene) INTERMEDIATE III.5: 2-[7-Hydroxy-3-(6-methoxypyridin-2-yl)-1-oxo-1 /-/-isoquinolin-2-yl]- Λ/-isopropylacetamide (from INTERMEDIATE II.2 & INTERMEDIATE 1.1 ) INTERMEDIATE III.6: Λ/-terf-Butyl-2-[7-hydroxy-3-(6-methoxypyridin-2-yl)-1-oxo-1 /-/- isoquinolin-2-yl]acetamide (from INTERMEDIATE II.2 & INTERMEDIATE I.2) Procedure III: Method B

INTERMEDIATE 111.7: 243-(3-Chlorophenyl)-7-hvdroxy-1-oxo-1 H-isoαuinolin-2-yl1-Λ/- isopropylacetamide

a) 2-[(E)-2-(3-Chlorophenyl)vinyl1-5-methoxybenzoic acid methyl ester

To a stirred solution of 2-bromo-5-methoxybenzoic acid methyl ester (17.7 g, 72.2 mmol) and 3-chlorovinylbenzene (9.17 ml_, 72.2 mmol) in anhydrous acetonitrile (180 ml_) was added triethylamine (20.10 ml_, 144 mmol) and tris(o-tolyl)phosphine (2.85 g, 9.38 mmol). The reaction mixture was sparged with argon for 5 min, palladium(ll) acetate (1.62 g, 7.22 mmol) was added and the mixture heated at 85 ⁰C under an argon atmosphere for 21 h. The product mixture was filtered through celite, concentrated in vacuo, the residue dissolved in ethyl acetate (400 ml_) and washed with 1 N HCI (aq.) (200 ml_) and brine (200 ml_). The combined aqueous layers were back-extracted with ethyl acetate (200 ml_). The ethyl acetate extracts were combined, dried (MgSO₄) and concentrated under reduced pressure to give the crude 2-[(E)-2-(3-chlorophenyl)vinyl]-5-methoxybenzoic acid methyl ester as a red-brown, viscous oil which was used in the next step without further purification. Data for 2-[(E)-2-(3-chlorophenyl)vinyl]-5-methoxybenzoic acid methyl ester: ¹H NMR (300 MHz, CDCI₃): δ 7.91 (d, 1 H), 7.63 (d, 1 H), 7.49 (dd, 1 H), 7.44 (d, 1 H), 7.41 (ddd, 1 H), 7.26 (d, 1 H), 7.21 (ddd, 1 H), 7.08 (dd, 1 H), 6.83 (d, 1 H), 3.94 (s, 3H), 3.86 (s, 3H) ppm. b) (F)-2-[2-(3-Chlorophenyl)vinyl1-5-methoxybenzoic acid

Crude 2-[(E)-2-(3-chlorophenyl)vinyl]-5-methoxybenzoic acid methyl ester was suspended in methanol:THF:water (3:1 :1 [v/v], 400 mL) and lithium hydroxide (12.10 g, 289 mmol) added. The mixture was stirred for 22 h at ambient temperature and concentrated in vacuo to give a pale brown solid. The crude product was re-dissolved in water (400 mL), the solution washed with diethyl ether (3 x 250 mL) and acidified to pH 2 with 1 N HCI (aq.). The aqueous was extracted with ethyl acetate (3 x 200 mL), the organic phase dried (MgSO₄) and concentrated in vacuo to give a tan solid which was triturated with methanol and filtered to give (E)-2-[2-(3-chlorophenyl)vinyl]-5-methoxybenzoic acid (15.43 g, 53.44 mmol, 74% for 2 steps from 2-bromo-5-methoxybenzoic acid methyl ester) as an off-white powder. Data for (E)-2-[2-(3-chlorophenyl)vinyl]-5-methoxybenzoic acid: ¹H NMR (300 MHz, (CDs)₂SO): δ 7.87 (d, 1 H), 7.76 (d, 1 H), 7.56 (dd, 1 H), 7.49 (ddd, 1 H), 7.40 (app t, 1 H), 7.35 (d, 1 H), 7.32 (ddd, 1 H), 7.17 (dd, 1 H), 7.05 (d, 1 H), 3.82 (s, 3H) ppm.

c) 3-(3-Chlorophenyl)-7-methoxyisochromen-1-one

A solution of (E)-2-[2-(3-chlorophenyl)vinyl]-5-methoxybenzoic acid (15.00 g, 51.95 mmol) in anhydrous THF (520 mL) was sparged with argon for 5 min. p-Benzoquinone (6.18 g, 57.20 mmol) was added followed by bis(acetonitrile)dichloropalladium(ll) (674 mg, 2.60 mmol) and the resultant mixture stirred at ambient temperature for 17 h. 1 N NaOH (aq.) (375 mL) was added and the resultant brown solid washed with chloroform (4 x 200 mL) to provide 3-(3-chlorophenyl)-7-methoxyisochromen-1-one (10.96 g, 38.23 mmol, 74%) as pale yellow solid. Data for 3-(3-chlorophenyl)-7-methoxyisochromen-1-one: ¹H NMR (300 MHz, CDCI₃): δ 7.86-7.84 (m, 1 H), 7.75-7.72 (m, 2H), 7.45 (d, 1 H), 7.43-7.36 (m, 2H), 7.33 (dd, 1 H), 6.94 (s, 1 H), 3.93 (s, 3H) ppm; MS (ESI) m/z: 287 ([M+H]⁺).

d) 2-[3-(3-Chlorophenyl)-7-methoxy-1-oxo-1 /-/-isoαuinolin-2-yl1-Λ/-isopropylacetamide

In an open, 50 ml_ two-necked round bottom flask, a neat mixture of compound 3-(3- chlorophenyl)-7-methoxyisochromen-1-one (1.00 g, 3.49 mmol) and 2-amino-Λ/- isopropylacetamide (INTERMEDIATE 1.1 ) (2.02 g, 17.4 mmol, 5 eq) was heated to 120 ⁰C under argon for 3 days, adding absolute EtOH in aliquots (2 ml_) daily to loosen up the reaction mixture. The residue was purified by chromatography on silica gel with ethyl acetate:hexane (1 :3, v/v) as eluent to give 2-[3-(3-chlorophenyl)-7-methoxy-1 -oxo-1 H- isoquinolin-2-yl]-N-isopropylacetamide (0.985 g, 2.56 mmol, 73 %) as a white solid. Data for 2-[3-(3-chlorophenyl)-7-methoxy-1 -oxo-1 H-isoquinolin-2-yl]-N- isopropylacetamide: ¹H NMR (300 MHz, CDCI₃): δ 7.82 (d, 1 H), 7.47-7.37 (m, 5 H), 7.29 (dd, 1 H), 6.47 (s, 1 H), 5.87 (br d, 1 H), 4.45 (s, 2 H), 4.06 (septet, 1 H), 3.94 (s, 3 H), 1.15 (d, 6 H) ppm; MS (ESI) m/z: 326 ([M-C₃H₈N]⁺), 385 ([M+H]⁺).

e) 2-[3-(3-Chlorophenyl)-7-hvdroxy-1 -oxo-1 /-/-isoαuinolin-2-yl1-Λ/-isopropylacetamide (INTERMEDIATE III.7)

A solution of 2-[3-(3-chlorophenyl)-7-methoxy-1 -oxo-1 /-/-isoquinolin-2-yl]-Λ/- isopropylacetamide (886 mg, 2.30 mmol) in dry DCM (25 ml_) was cooled to -78 ⁰C and a solution of BBr₃ (1 M in DCM, 20.3 ml_, 20.3 mmol) was added dropwise. After 1 h, the cooling bath was removed and the mixture was allowed to stir an additional 17.5 h, then cooled to 0 ⁰C and quenched by dropwise addition of sat. NaHCO₃ (aq.) (15 ml_). The aqueous mixture was extracted with IPA:DCM (1 :3, v/v) (4 x 25 ml_). The combined organic extracts were washed with brine (25 ml_), dried (MgSO₄) and concentrated to give the crude product, which was recrystallized from EtOH to give pure 2-[3-(3-chlorophenyl)- 7-hydroxy-1 -oxo-1 H-isoquinolin-2-yl]-N-isopropylacetamide (INTERMEDIATE IHJ) (530 mg, 1.43 mmol, 62 %) as white solid.

Data for 2-[3-(3-chlorophenyl)-7-hydroxy-1 -oxo-1 H-isoquinolin-2-yl]-N-isopropylacetamide (INTERMEDIATE III J): ¹H NMR (300 MHz, cf-DMSO): δ 10.02 (s, 1 H), 7.83 (d, 1 H), 7.55-7.39 (m, 5 H), 7.42-7.39 (m, 1 H), 7.21 (dd, 1 H), 6.49 (s, 1 H), 4.33 (s, 2 H), 3.77 (septet, 1 H), 0.99 (d, 6 H) ppm; MS (ESI) m/z: 312 ([M-C₃H₈N]⁺), 371 ([M+H]⁺), 763 ([2Mn-Na]⁺).

Similarly prepared were:

INTERMEDIATE III.8: Λ/-terf-Butyl-2-[3-(3-chlorophenyl)-7-hydroxy-1-oxo-1 /-/-isoquinolin- 2-yl]acetamide (from INTERMEDIATE I.2 and 3-chlorostyrene) INTERMEDIATE III.9: 2-[3-(3-Fluorophenyl)-7-hydroxy-1-oxo-1 H-isoquinolin-2-yl]-Λ/- isopropylacetamide (from INTERMEDIATE 1.1 and 3-fluorostyrene) INTERMEDIATE 111.10: 2-(7-Hydroxy-1-oxo-3-phenyl-1 H-isoquinolin-2-yl)-Λ/- isopropylacetamide (from INTERMEDIATE 1.1 and styrene)

INTERMEDIATE 111.1 1 : Λ/-terf-Butyl-2-[3-(3-chloro-4-fluorophenyl)-7-hydroxy-1-oxo-1 H- isoquinolin-2-yl]acetamide (from INTERMEDIATE II.3 & INTERMEDIATE I.2)

Synthesis of Examples According to the Invention

EXAMPLE 1 : 2-[3-(3-Chlorophenyl)-7-((S)-2-methyl-3-pyrrolidin-1-ylpropoxy)-1-oxo-1 /-/- isoguinolin-2-yl1-Λ/-isopropylacetamide

a) 2-[3-(3-Chlorophenyl)-7-((S)-3-hvdroxy-2-methylpropoxy)-1-oxo-1 /-/-isoguinolin-2-yl1-Λ/- isopropylacetamide

A suspension of 2-[3-(3-chlorophenyl)-7-hydroxy-1-oxo-1 /-/-isoquinolin-2-yl]-Λ/- isopropylacetamide (INTERMEDIATE III.7) (347 mg, 0.936 mmol), K₂CO₃ (674 mg, 4.68 mmol) and (S)-(+)-3-bromo-2-methyl-1-propanol (0.48 ml_, 4.7 mmol) in dry acetonitrile (5 ml_) was stirred for 18 h at 80 ⁰C. The resultant mixture was poured into H₂O (20 ml_), cooled to 0 ⁰C and filtered. The precipitate was washed with cold H₂O and dried in vacuo to furnish 2-[3-(3-chlorophenyl)-7-((S)-3-hydroxy-2-methylpropoxy)-1-oxo-1H-isoquinolin- 2-yl]-N-isopropylacetamide (382 mg, 0.862 mmol, 92%) as white solid. Data for 2-[3-(3-chlorophenyl)-7-((S)-3-hydroxy-2-methylpropoxy)-1-oxo-1H-isoquinolin-2- yl]-N-isopropylacetamide: ¹H NMR (300 MHz, cf-DMSO): δ 7.87 (d, 1 H), 7.64 (d, 1 H),- 7.62 (d, 1 H), 7.57-7.51 (m, 3 H), 7.44 (dd, 1 H), 7.38 (dd, 1 H), 6.57 (s, 1 H), 4.66 (br s, 1 H), 4.37 (s, 2 H), 4.09 (dd, 1 H), 3.92 (dd, 1 H), 3.78 (septet, 1 H), 3.46-3.45 (m, 2 H), 2.08-2.02 (m, 1 H), 1.00 (d, 6 H), 1.00 (d, 3 H) ppm; MS (ESI) m/z: 384 ([M-C₃H₈N]⁺), 443 ([MH-H]⁺), 907 ([2M+Na]⁺). b) Methanesulfonic acid (RVS-fS-O-chlorophenvD^-dsopropylcarbamoylmethvπ-i-oxo- 1 ,2-dihvdroisoαuinolin-7-yloxy1-2-methylpropyl ester

A suspension of 2-[3-(3-chlorophenyl)-7-((S)-3-hydroxy-2-methylpropoxy)-1-oxo-1 H- isoquinolin-2-yl]-N-isopropylacetamide (319 mg, 0.720 mmol) and triethylamine (0.30 ml_, 2.16 mmol) in dry DCM (7.0 ml_) was cooled to 0 ⁰C and methanesulfonyl chloride (67 μl_, 0.86 mmol) was added dropwise via a syringe. The mixture was stirred for 1 h at 0 ⁰C, a second aliquot of methanesulfonyl chloride (25 μl_, 0.32 mmol) was added, and stirring was continued 30 min at room temperature. The mixture was diluted with ethyl acetate (20 mL) and washed with 1 N HCI (aq.) (20 ml_), sat. NaHCO₃ (aq.) (20 mL) and brine (20 ml_). The aqueous washes were back-extracted with ethyl acetate (20 mL), and the combined organic extracts were dried (MgSO₄) and concentrated to give crude methanesulfonic acid (R)-3-[3-(3-chlorophenyl)-2-(isopropylcarbamoylmethyl)-1-oxo-1, 2- dihydroisoquinolin-7-yloxy]-2-methylpropyl ester (316 mg, 0.720 mmol, 84%) as off-white solid.

Data for methanesulfonic acid (R)-3-[3-(3-chlorophenyl)-2-(isopropylcarbamoylmethyl)-1- oxo-1, 2-dihydroisoquinolin-7-yloxy]-2-methylpropyl ester: ¹H NMR (300 MHz, CDCI₃): δ 7.80 (d, 1 H), 7.47-7.37 (m, 5 H), 7.29 (dd, 1 H), 6.46 (s, 1 H), 5.82 (br d, 1 H), 4.44 (s, 2 H), 4.33 (d, 2 H), 4.13-4.01 (m, 3 H), 3.00 (s, 3 H), 2.50-2.43 (m, 1 H), 1.15 (d, 6 H), 1.15 (d, 3 H) ppm; MS (ESI) m/z: 462 ([M-C₃H₈N]⁺), 521 ([M+H]⁺).

c) 2-[3-(3-Chlorophenyl)-7-((S)-2-methyl-3-pyrrolidin-1-ylpropoxy)-1-oxo-1 /-/-isoαuinolin-2- yl1-Λ/-isopropylacetamide (EXAMPLE 1 )

To a stirred suspension of methanesulfonic acid (R)-3-[3-(3-chlorophenyl)-2- (isopropylcarbamoylmethyl)-1-oxo-1 ,2-dihydroisoquinolin-7-yloxy]-2-methylpropyl ester (310 mg, 0.595 mmol) in dry acetonitrile (3 mL) was added K₂CO₃ (412 mg, 2.98 mmol) and pyrrolidine (150 mL, 1.78 mmol). The mixture was heated at reflux temperature for 6 h and water (10 mL) was added. The resultant suspension was extracted with ethyl acetate (3 x 25 mL), and the combined organic extracts were dried (MgSO₄) and concentrated in vacuo. Purification by chromatography on silica gel with MeOH:DCM:NH₄OH (aq.) (1 :18.9:0.1 v/v) gave 2-[3-(3-chlorophenyl)-7-((S)-2-methyl-3-pyrrolidin-1-ylpropoxy)-1- oxo-1H-isoquinolin-2-yl]-N-isopropylacetamide (EXAMPLE 1) (146 mg, 0.294 mmol, 67%). Data for 2-[3-(3-chlorophenyl)-7-((S)-2-methyl-3-pyrrolidin-1 -ylpropoxy)-1 -oxo-1 H- isoquinolin-2-yl]-N-isopropylacetamide (EXAMPLE 1): ¹H NMR (300 MHz, CDCI₃): δ 7.83 (d, 1 H), 7.47-7.37 (m, 5 H), 7.30 (dd, 1 H), 6.46 (s, 1 H), 5.91 (br d, 1 H), 4.45 (s, 2 H), 4.15 (dd, 1 H), 4.07 (septet, 1 H), 3.91 (dd, 1 H), 2.62-2.46 (br m, 5 H), 2.36 (dd, 1 H), 2.21 (dd, 1 H), 1.80-1.76 (br m, 4 H), 1.16 (d, 6 H), 1.1 1 (d, 3 H) ppm; MS (ESI) m/z: 496 ([MH-H]⁺), 991 ([2M+H]⁺), 1013 ([2M+Na]⁺).

The following compounds (EXAMPLES 2-14) were prepared in a similar manner from INTERMEDIATES III.

EXAMPLE 2: 2-[7-((S)-3-Diethylamino-2-methylpropoxy)-3-(3-fluorophenyl)-1-oxo-1 /-/- isoαuinolin-2-yl1-Λ/-isopropylacetamide

MS (ESI) m/z: 482 ([M+H]⁺) (from INTERMEDIATE 111.9 & diethylamine)

EXAMPLE 3: 247-((S)-3-Dimethylamino-2-methylpropoxy)-3-(3-fluorophenyl)-1-oxo-1 /-/- isoαuinolin-2-yl1-Λ/-isopropylacθtamide

MS (ESI) m/z: 454 ([M+H]⁺) (from INTERMEDIATE 111.9 & dimethylamine)

EXAMPLE 4: 2-[7-[(S)-3-(Ethylmethylamino)-2-methylpropoxyl-3-(3-methoxyphenyl)-1- oxo-1 /-/-isoαuinolin-2-yl1-Λ/-isopropylacetamide

MS (ESI) m/z: 480 ([M+H]⁺) (from INTERMEDIATE III.3 & N-methylethylamine)

EXAMPLE 5: 2-[3-(3-Fluorophenvn-7-((S)-2-methyl-3-pyrrolidin-1 -ylpropoxyM -oxo-1 H- isoαuinolin-2-yl1-Λ/-isopropylacθtamide

MS (ESI) m/z: 480 ([M+H]⁺) (from INTERMEDIATE III.9 & pyrrolidine) EXAMPLE 6: 2-[3-(3-)-7-((S)-3-dimethylamino-2-methylpropoxy)-1-oxo-1 /-/-isoαuinolin-2- yl1-Λ/-isopropylacetamide

MS (ESI) m/z: 470/472 ([M+H]⁺) (from INTERMEDIATE 111.7 & dimethylamine)

EXAMPLE 7: 2-[7-((S)-3-Azetidin-1-yl-2-methylpropoxy)-3-(3-methoxyphenyl)-1-oxo-1 /-/- isoαuinolin-2-yl1-Λ/-isopropylacetamide

MS (ESI) m/z: 478 ([M+H]⁺) (from INTERMEDIATE III.3 & azetidine)

EXAMPLE 8: 2-[7-[(S)-3-(lsobutylmethylamino)-2-methylpropoxy1-3-(3-methoxyphenyl)-1- oxo-1 /-/-isoαuinolin-2-yl1-Λ/-isopropylacetamide

MS (ESI) m/z: 508 ([M+H]⁺) (from INTERMEDIATE III.3 & N-methylisobutylamine)

EXAMPLE 9: 2-[7-((S)-3-Diethylamino-2-methylpropoxy)-3-(3-methoxyphenyl)-1-oxo-1 /-/- isoαuinolin-2-yl1-Λ/-isopropylacetamide

MS (ESI) m/z: 494 ([M+H]⁺) (from INTERMEDIATE 111.3 & diethylamine)

EXAMPLE 10: Λ/-lsopropyl-2-[3-(3-methoxyphenyl)-7-((S)-2-methyl-3-pyrrolidin-1- ylpropoxy)-1 -oxo-1 /-/-isoαuinolin-2-yliacetamide

MS (ESI) m/z: 492 ([M+H]⁺) (from INTERMEDIATE 111.3 & pyrrolidine)

EXAMPLE 1 1 : Λ/-lsopropyl-2-[7-[(S)-3-(isopropylmethylamino)-2-methylpropoxy1-3-(3- methoxyphenyl)-1 -oxo-1 /-/-isoαuinolin-2-yliacetamide

MS (ESI) m/z: 494 ([M+H]⁺) (from INTERMEDIATE 111.3 & N-methylisopropylamine)

EXAMPLE 12: 2-[3-(3-Fluorophenyl)-7-((S)-2-methyl-3-piperidin-1-ylpropoxy)-1-oxo-1 /-/- isoαuinolin-2-yl1-Λ/-isopropylacetamide

MS (ESI) m/z: 494 ([M+H]⁺) (from INTERMEDIATE 111.9 & piperidine)

EXAMPLE 13: 2-[7-((S)-3-Dimθthylamino-2-methylpropoxy)-3-(3-methoxyphenyl)-1-oxo- 1 /-/-isoαuinolin-2-yl1-Λ/-isopropylacetamide

MS (ESI) m/z: 466 ([M+H]⁺) (from INTERMEDIATE 111.3 & dimethylamine)

EXAMPLE 14: Λ/-lsopropyl-2-[3-(3-methoxyphenvn-7-((S)-2-methyl-3-piperidin-1- ylpropoxy)-1 -oxo-1 /-/-isoαuinolin-2-yliacetamide

MS (ESI) m/z: 506 ([M+H]⁺) (from INTERMEDIATE 111.3 & piperidine)

EXAMPLE 15: Λ/-terf-Butyl-2-[3-(4-fluoro-3-methoxyphenyl)-1-oxo-7-(3-pyrrolidin-1- ylpropoxy)-1/-/-isoαuinolin-2-yl1acetamide

To a solution of Λ/-terf-butyl-2-[3-(4-fluoro-3-methoxyphenyl)-7-hydroxy-1-oxo-1/-/- isoquinolin-2-yl]acetamide (INTERMEDIATE 111.1 ) (25 mg, 0.063 mmol) in anhydrous acetonitrile (5 ml_) were added K₂CO₃ (26 mg, 0.189 mmol) and 1-bromo-3-chloropropane (6.2 uL, 0.63 mmol). The reaction mixture was heated at reflux temperature for 16 h. Pyrrolidine (53 uL, 0.63 mmol) and additional K₂CO₃ (26 mg, 0.189 mmol) were added and the reaction mixture was heated at reflux temperature for 48 h. The reaction mixture was filtered and the filtrate concentrated in vacuo. The crude residue was purified by preparative HPLC to afford N-tert-butyl-2-[3-(4-fluoro-3-methoxyphenyl)-1-oxo-7-(3- pyrrolidin-1-ylpropoxy)-1H-isoquinolin-2-yl]acetamide (EXAMPLE 15) hydrochloride salt (4.4 mg, 0.008 mmol, 13%) as an HCI salt.

Data for N-tert-butyl-2-[3-(4-fluoro-3-methoxyphenyl)-1 -oxo-7-(3-pyrrolidin-1 -ylpropoxy)- 1H-isoquinolin-2-yl]acetamide (EXAMPLE 15) hydrochloride salt: ¹H NMR (400 MHz, CD₃OD): δ 7.76 (d, 1 H), 7.62 (d, 2 H), 7.38 (dd, 1 H), 7.25-7.15 (m, 2 H), 7.00 (m, 1 H), 6.61 (s, 1 H), 4.53 (s, 2 H), 4.25 (t, 2 H), 3.86 (s, 3 H), 3.73 (m, 2 H), 3.46 (m, 2 H), 3.15 (m, 2 H), 2.30 (m, 2 H), 2.19 (m, 2 H), 2.06-1.98 (m, 2 H), 1.29 (s, 9 H) ppm; MS (ESI) m/z: 510 ([M+H]⁺), 1018 ([2M+H]⁺).

The following compounds (EXAMPLES 16-34) were prepared in a similar manner from INTERMEDIATES III:

EXAMPLE 16: 2 -[3-(4-Fluoro-3-methoxyphenyl)-1 -oxo-7-(3-pyrrolidin-1 -ylpropoxy)-1 H- isoαuinolin-2-yl1-Λ/-isopropylacetamide

MS (ESI) m/z: 496 ([M+H]⁺) (from INTERMEDIATE 111.2 & pyrrolidine)

EXAMPLE 17: Λ/-terf-Butyl-2-(3-(3-Chlorophenyl)-7-[3-(4-hvdroxypiperidin-1-yl)-propoxy1- 1-oxo-1 /-/-isoαuinolin-2-yl)-acetamide

MS (ESI) m/z: 526/528 ([M+H]⁺) (from INTERMEDIATE III.8 & 4-hydroxypiperidine)

EXAMPLE 18: Λ/-lsopropyl-2-[3-(3-methoxyphenyl)-1-oxo-7-(3-pyrrolidin-1-ylpropoxy)-1 /-/- isoαuinolin-2-yli-acetamide

MS (ESI) m/z: 478 ([M+H]⁺) (from INTERMEDIATE 111.3 & pyrrolidine)

EXAMPLE 19: Λ/-lsopropyl-2-[3-(3-methoxyphenyl)-1-oxo-7-(3-piperidin-1-ylpropoxy)-1 /-/- isoαuinolin-2-yli-acetamide

MS (ESI) m/z: 492 ([M+H]⁺) (from INTERMEDIATE 111.3 & piperidine)

EXAMPLE 20: 247-(3-Diethylaminopropoxy)-3-(3-methoxyphenyl)-1-oxo-1 H-isoαuinolin-2- yl1-Λ/-isopropylacetamide

MS (ESI) m/z: 480 ([M+H]⁺) (from INTERMEDIATE 111.3 & diethylamine)

EXAMPLE 21 : 2-[3-(3-Chlorophenyl)-1-oxo-7-(3-piperidin-1-ylpropoxy)-1 /-/-isoαuinolin-2- yl1-Λ/-isopropylacetamide

MS (ESI) m/z: 496([M+H]⁺) (from INTERMEDIATE 111.7 & piperidine)

EXAMPLE 22: 2-[7-(3-Dimethylaminopropoxy)-3-(3-methoxyphenyl)-1-oxo-1 /-/-isoαuinolin- 2-yl1-Λ/-isopropylacetamide

MS (ESI) m/z: 452 ([M+H]⁺) (from INTERMEDIATE 111.3 & dimethylamine)

EXAMPLE 23: Λ/-terf-Butyl-2-[3-(6-methoxypyridin-2-yl)-1-oxo-7-(3-pyrrolidin-1-ylpropoxy)- 1 /-/-isoαuinolin-2-yliacetamide

MS (ESI) m/z: 493 ([M+H]⁺) (from INTERMEDIATE 111.6 & pyrrolidine)

EXAMPLE 24: Λ/-terf-Butyl-2-[3-(3-Chlorophenyl)-1-oxo-7-(3-pyrrolidin-1-ylpropoxy)-1 /-/- isoαuinolin-2-yliacetamide

MS (ESI) m/z: 496/498 ([M+H]⁺) (from INTERMEDIATE 111.8 & pyrrolidine)

EXAMPLE 25: 2-[3-(3-Chlorophenyl)-1-oxo-7-(3-pyrrolidin-1-ylpropoxy)-1 /-/-isoαuinolin-2- yl1-Λ/-isopropylacetamide

MS (ESI) m/z: 482/484 ([M+H]⁺) (from INTERMEDIATE 111.7 & pyrrolidine)

EXAMPLE 26: Λ/-lsopropyl-2-[1-oxo-3-phenyl-7-(3-piperidin-1-ylpropoxy)-1 /-/-isoαuinolin-2- yliacetamide

MS (ESI) m/z: 462 ([M+H]⁺) (from INTERMEDIATE 111.10 & piperidine)

EXAMPLE 27: Λ/-terf-Butyl-2-[3-(3-chloro-4-fluorophenyl)-1-oxo-7-(3-piperidin-1- ylpropoxy)-1 /-/-isoαuinolin-2-yl1acetamide

MS (ESI) m/z: 528/530 ([M+H]⁺) (from INTERMEDIATE 111.1 1 & piperidine)

EXAMPLE 28: Λ/-terf-Butyl-2-[3-(3-chloro-4-fluorophenyl)-1-oxo-7-(3-pyrrolidin-1- ylpropoxy)-1 /-/-isoαuinolin-2-yl1acetamide

MS (ESI) m/z: 514/516 ([M+H]⁺) (from INTERMEDIATE 111.1 1 & pyrrolidine)

EXAMPLE 29: Λ/-lsopropyl-2-[3-(6-methoxypyridin-2-yl)-1-oxo-7-(3-pyrrolidin-1-ylpropoxy)- 1 /-/-isoαuinolin-2-yliacetamide

MS (ESI) m/z: 479 ([M+H]⁺) (from INTERMEDIATE 111.5 & pyrrolidine)

EXAMPLE 30: Λ/-terf-Butyl-2-[3-(3-methoxyphenyl)-1-oxo-7-(3-pyrrolidin-1-ylpropoxy)-1 /-/- isoαuinolin-2-yliacetamide

MS (ESI) m/z: 492 ([M+H]⁺) (from INTERMEDIATE 111.4 & pyrrolidine)

EXAMPLE 31 : 2-{3-(3-Chlorophenyl)-7-[3-(4-hvdroxy-4-methyl-piperidin-1-yl)-propoxy1-1- oxo-1 /-/-isoαuinolin-2-yl)-Λ/-isopropylacetamide

MS (ESI) m/z: 526/528 ([M+H]⁺) (from INTERMEDIATE 111.7 & 4-hydroxy-4- methylpiperidine)

EXAMPLE 32: A/-tert-Butyl-2-f3-(3-Chlorophenyl)-7-f3-(4-hvdroxy-4-methyl-piperidin-1-yl)- propoxy1-1-oxo-1 /-/-isoαuinolin-2-yl)acetamide

MS (ESI) m/z: 540/542 ([M+H]⁺) (from INTERMEDIATE III.8 & 4-hydroxy-4- methylpiperidine)

EXAMPLE 33: 2-[7-[3-(4-Hvdroxy-4-methylpiperidin-1-yl)-propoxy1-3-(3-methoxyphenyl)-1- oxo-1 /-/-isoαuinolin-2-yl1-Λ/-isopropylacetamide

MS (ESI) m/z: 522 ([M+H]⁺) (from INTERMEDIATE III.3 & 4-hydroxy-4-methylpiperidine)

EXAMPLE 34: Λ/-terf-Butyl-2-[7-[3-(4-hvdroxy-4-methylpiperidin-1-yl)propoxy1-3-(3- methoxyphenyl)-1 -oxo-1 /-/-isoαuinolin-2-yliacetamide

MS (ESI) m/z: 522 ([M+H]⁺) (from INTERMEDIATE 111.4 & 4-hydroxy-4-methylpiperidine)

EXAMPLE 35: 2-r3-(3-Chlorophenyl)-1-oxo-7-(3-piperidin-1-ylmethylphenyl)-1 A7- isoαuinolin-2-yl1-Λ/-isopropylacetamide

a) Trifluoromethanesulfonic acid S-O-chlorophenvD^-dsopropylcarbamoylmethyD-i-oxo- 1 ,2-dihvdroisoαuinolin-7-yl ester

To 2-[3-(3-chlorophenyl)-7-hydroxy-1 -oxo-1 /-/-isoquinolin-2-yl]-Λ/-isopropylacetamide

(INTERMEDIATE III.7) (0.60 g, 1.6 mmol) in dry pyridine (15 mL) at 0 ⁰C was added trifluoromethanesulfonic anhydride (0.27 mL, 1.6 mmol) dropwise. After the addition the ice bath was removed and the reaction mixture was stirred for 2 h at room temperature. The mixture was then concentrated in vacuo and the crude residue taken up in EtOAc and washed with 1 N HCI (aq.) (1 X 20 ml_) and brine (1 X 20 ml_). The organic phase was dried (MgSO₄), filtered and concentrated in vacuo to afford trifluoromethanesulfonic acid 3-(3-chlorophenyl) -2-(isopropylcarbamoyl methyl) - 1 -oxo-1, 2-dihydroisoquinolin- 7-yl ester (0.66 g, 1.3 mmol, 82%) as an orange solid, which was used without further purification. Data for trifluoromethanesulfonic acid 3-(3-chlorophenyl)-2-(isopropylcarbamoylmethyl)-1- oxo-1, 2-dihydroisoquinolin-7-yl ester: MS (ESI), m/z: 444/446 ([M-C₃H₈N]⁺).

b) 2-[3-(3-Chlorophenyl)-7-(3-hvdroxymethylphenyl)-1 -oxo-1 /-/-isoquinolin-2-yli-Λ/- isopropylacetamide

To a solution of trifluoromethanesulfonic acid 3-(3-chlorophenyl)-2- (isopropylcarbamoylmethyl)-i -oxo-1 ,2-dihydroisoquinolin-7-yl ester (0.10 g, 0.20 mmol) in acetone (2ml_) and water (1 ml_) was added 3-hydroxymethylphenyl boronic acid (0.10 g, 0.65 mmol), K₂CO₃ (100 mg, 0.72 mmol) and (Ph₃P)₄Pd (20 mg, 0.017 mmol). The vessel was sealed and heated at 60 ⁰C for 1 hour. The mixture was cooled to 0 ⁰C and 2-[3-(3- chlorophenyl)-7-(3-hydroxymethylphenyl)-1 -oxo-1 H-isoquinolin-2-yl]-N-isopropylacetamide was collected by filtration and used in the next step without further purification. Data for 2-[3-(3-chlorophenyl)-7-(3-hydroxymethylphenyl)-1 -oxo-1 H-isoquinolin-2-yl]-N- isopropylacetamide: MS (ESI) m/z: 461/463 ([M+H]⁺ ).

c) 2-[7-(3-Chloromethylphenyl)-3-(3-chlorophenyl)-1 -oxo-1 /-/-isoαuinolin-2-yli-Λ/- isopropylacetamide

To a solution of crude 2-[3-(3-chlorophenyl)-7-(3-hydroxymethylphenyl)-1-oxo-1 H- isoquinolin-2-yl]-N-isopropylacetamide (100 mg, 0.22 mmol) in DCM (5 ml_) was added SOCI₂ (0.5 ml_, 6.8 mmol) and the reaction mixture was stirred at 23 ⁰C for 2 h. The solution was concentrated in vacuo and the crude residue purified by chromatography on silica gel with MeOH: DCM (1 :19, v/v) as eluent to yield 2-[7-(3-chloromethylphenyl)-3-(3- chlorophenyl)-1-oxo-1H-isoquinolin-2-yl]-N-isopropylacetamide (19 mg, 0.40 mmol, 20% for 2 steps from trifluoromethanesulfonic acid 3-(3-chlorophenyl)-2- (isopropylcarbamoylmethyl)-1-oxo-1 ,2-dihydroisoquinolin-7-yl ester as yellow solid.

d) 2 -[3-(3-Chlorophenyl)-1-oxo-7-(3-piperidin-1-ylmethylphenyl)-1 /-/-isoquinolin-2-yl1-Λ/- isopropylacetamide (EXAMPLE 35)

To 2-[7-(3-chloromethylphenyl)-3-(3-chlorophenyl)-1-oxo-1 H-isoquinolin-2-yl]-N- isopropylacetamide (19 mg, 0.04 mmol) in DCM (5 ml_) was added piperidine (0.5 ml_) and this was stirred at 23 ⁰C for 18 h. The mixture was concentrated in vacuo, and the crude residue purified by preparative HPLC to yield the HCI salt of 2-[3-(3-chlorophenyl)- 1 -OXO- 7-(3-piperidin- 1 -ylmethylphenyl) - 1 H-isoquinolin-2-yl]-N-isopropylacetamide (EXAMPLE 35) hydrochloride salt (7 mg, 0.013 mmol, 33%) as pale beige solid. Data for 2-[3-(3-chlorophenyl)-1 -oxo-7-(3-piperidin-1 -ylmethylphenyl) -1 H-isoquinolin-2-yl]- N-isopropylacetamide (EXAMPLE 35) hydrochloride salt: ¹H NMR (300 MHz, CD₃OD) δ 8.64 (d, 1 H), 8.2-7.4 (m, 1 1 H), 6.71 (s, 1 H), 4.59 (s, 2 H), 4.42 (s, 2 H), 3.95 (septet, 1 H), 3.54 (br d, 2 H), 3.05 (br t, 2 H) 2.0-1.5 (m, 6 H), 1.1 1 (d, 6 H) ppm; MS (ESI) m/z:

EXAMPLE 36 was prepared in a similar manner:

EXAMPLE 36: Λ/-ferf-Butyl-2-[3-(3-methoxyphenyl)-1-oxo-7-(3-piperidin-1- ylmethylphenyl)-1 /-/-isoαuinolin-2-yl1acetamide

MS (ESI) m/z: 538 ([M+H]⁺) (from INTERMEDIATE 111.4 & piperidine)

EXAMPLE 37:

Chinese Hamster Ovary (CHO) cells stably expressing the human V₃ receptor were incubated to equilibrium with the test compound (at a final assay concentration of 10^'10 mol.L ¹ to 10^~5 mol.L ¹) and [³H]AVP (at a final assay concentration of 2.5 x 10^~9 mol.L ¹). Throughout the concentration of dimethylsulphoxide (DMSO) did not exceed 0.1 % (v/v).

After washing with ice-cold phosphate buffered saline (PBS), scintillation fluid was added and the plates counted on a Topcount NXT apparatus.

A sigmoidal dose response curve (non-linear regression, variable slope) was plotted as concentration of test compound (mol.L ¹) against percentage specific binding of [³H]AVP and a K, value was calculated. Each determination was carried out in triplicate and repeated on at least 3 separate occasions

Table 1 shows the binding activity obtained for some representative compounds of the invention.

Table 1 V₃ binding activity for compounds according to the invention EXAMPLE 3: 2-[7-((S)-3- ++ Dimethylamino-2-methylpropoxy)-3- (3-fluorophenyl)-1 -oxo-1 /-/-isoquinolin- 2-yl]-Λ/-isopropylacetamide

EXAMPLE 14: Λ/-lsopropyl-2-[3-(3- methoxyphenyl)-7-((S)-2-methyl-3- piperidin-1-ylpropoxy)-1-oxo-1 AV- isoquinolin-2-yl]acetamide

EXAMPLE 23: Λ/-terf-Butyl-2-[3-(6- ++ methoxypyridin-2-yl)-1-oxo-7-(3- pyrrolidin-1-ylpropoxy)-1 /-/-isoquinolin- 2-yl]acetamide

EXAMPLE 26: Λ/-lsopropyl-2-[1-oxo- +++ 3-phenyl-7-(3-piperidin-1-ylpropoxy)- 1 /-/-isoquinolin-2-yl]acetamide

EXAMPLE 28: Λ/-ferf-Butyl-2-[3-(3- chloro-4-fluorophenyl)-1-oxo-7-(3- pyrrolidin-1-ylpropoxy)-1 /-/-isoquinolin- 2-yl]acetamide

+++ 0-1OnM ++ 10-10OnM + 10OnM-I uM

The ability of compounds of the invention to act as V₃ antagonists in a physiologically relevant system was determined by measuring their ability to block the release of adrenocorticotropic hormone (ACTH) from anterior pituitary corticotrophs in response to treatment with arginine vasopressin (AVP). Anterior pituitary corticotrophs were prepared from adult female Sprague-Dawley rats and seeded into 48 well plates. The cells were cultured for 4 days prior to exposure to compound. Test compounds were prepared at 10^~5 mol.L^'1 in 100% DMSO. Cells were exposed to a dose response of test compounds for 20 minutes (10^"8 mol.L^'1 - 10⁵ mol.L^'1). The final concentration of DMSO in the assay was kept constant at 0.3%. The cells were then exposed to 3 x 10^~9 mol.L^'1 AVP for 120 minutes. Supematants were harvested and stored at -2O⁰C. ACTH levels were subsequently measured by ELISA following the manufacturer's instructions (Immunodiagnostic systems, UK (Cat No. DX-SDX018)). Each treatment was carried out in quadruplicate and a mean value obtained for the amount of ACTH released. The degree of antagonism was then calculated as a percentage of the amount of ACTH released by agonist alone after adjustment for basal levels of ACTH. A PlC₅₀ was calculated by fitting a Sigmoidal dose response (variable slope) curve with a non-linear (fit) to the data using the software package GraphPad prism. Each determination was repeated on at least 3 separate occasions

Table 2 shows the activity obtained for some representative compounds of the invention. Table 2 V^ receptor antagonism in isolated rat anterior pituitary cells for compounds according to the invention

EXAMPLE 1 : 2-[3-(3- +

Chlorophenyl)-7-((S)-2-methyl-3- pyrrolidin-1-ylpropoxy)-1-oxo-1 /-/- isoquinolin-2-yl]-Λ/- isopropylacetamide

EXAMPLE 17: Λ/-ferf-Butyl-2-{3-(3- + + chlorophenyl)-7-[3-(4- hydroxypiperidin-1-yl)-propoxy]-1- oxo-1 /-/-isoquinolin-2-yl}-acetamide

++ 10-10OnM + 10OnM-I uM

Claims

Claims:

1. A 2-(1-oxo-1 /-/-isoquinolin-2-yl)acetamide derivative of formula I,

formula I wherein R¹ is C_1-6alkyl, C₃-₆cycloalkyl, Cs-ecycloalkylC^alkyl, C_∑-ealkenyl or C_∑-ealkynyl, said C_1- ₆alkyl, C₃-₆cycloalkyl and Cs-ecycloalkylC^alkyl being optionally substituted with one or more halogens; R² is Ce-^aryl optionally substituted with one to three substituents selected from halogen, hydroxy, cyano, C^alkyl, C₃.₆cycloalkyl, C^alkyloxy and C₃.₆cycloalkyloxy, said C₁.

₆alkyl, C₃-e cycloalkyl, C_1-6 alkyloxy and C^ecycloalkyloxy being optionally substituted with one or more halogens or R² is a 5-10 membered heteroaryl ring system comprising a heteroatom selected from N, O, S and optionally substituted with a substituent selected from methyl, C^alkyloxy and halogen;

R³ is an optional substituent selected from Ci_-6alkyl, C^alkyloxy and halogen, said C₁.

₆alky and C^alkyloxy being optionally substituted with one or more halogens; R⁴ is a group located at the 6- or 7- position of the oxoisoquinoline ring and is selected from

each R⁵ is independently H or Ci_₆alkyl or one of R⁵ when joined together with one of R⁶ or

R⁷ forms a 4-7 membered heterocyclic ring;

R⁶ and R⁷ are independently H, C_1-6alkyl, C₃-₆cycloalkyl, C₃-₆cycloalkylCi.₂alkyl, C_6-io aryl or C₆-ioarylCi-₂alkyl; or R⁶ and R⁷ together with the nitrogen to which they are bonded form a 4 to 8 membered saturated or unsaturated heterocyclic ring optionally comprising a further heteroatomic moiety selected from O, S and NR¹⁰, said heterocyclic ring being optionally substituted with one or two substituents selected from halogen, hydroxyl, Ci_₆alkyl, Ci_₆alkyloxy, cyano and COOR¹¹ and said heterocyclic ring being optionally fused at two adjacent carbon atoms to a phenyl ring; or one of R⁶ and R⁷ when joined together with one of R⁵ forms a 4-7 membered heterocyclic ring; or one of R⁶ and R⁷ when joined together with one of R⁸ forms a 5-6 membered heterocyclic ring; R⁸ is one or two substituents selected from H, Ci_₆alkyl, Ci_₆alkyloxy and halogen or one of R⁸ when joined together with one of R⁶ and R⁷ forms a 5-6 membered heterocyclic ring; or one of R⁸ when joined together with R⁹ forms a 5-6 membered ring R⁹ is H or Ci-ealkyl or R⁹ when joined together with one of R⁸ forms a 5-6 membered ring; R¹⁰ is H, C_1-6alkyl or d_-6acyl; R¹¹ is H or Ci-βalkyl; m is 2-4; n is 1-3;

X iS CH₂, O, S, SO₂ Or NR¹²; R¹² is H, C_1-6alkyl, C_1-6acyl or C₆-ioarylCi_₂alkyl group, said C₆-ioarylCi_₂alkyl group being optionally substituted with methyl or methoxy; Y is CH₂, (CH₂)₂ or (CH₂)₃;

Q, T, V and W are C or N with the proviso that one of Q, T, V and W is N and the others are C; Q', T and V are selected from C, O, N and S with the proviso that one of Q', T and V is O, N, or S and the others are C; or a pharmaceutically acceptable salt or solvate thereof.

2. The 2-(1-oxo-7/-/-isoquinolin-2-yl)acetamide derivative according to claim 1 , wherein R¹ is isopropyl, isobutyl, tertiary-butyl or cyclopropylmethyl.

3. The 2-(1-oxo-7/-/-isoquinolin-2-yl)acetamide derivative according to claim 1 or claim 2, wherein R² is a substituted phenyl ring selected from 3-chlorophenyl, 3-fluorophenyl, 3- methoxyphenyl, 3-trifluoromethoxyphenyl, 3-chloro-4-fluorophenyl and 4-fluoro-3- methoxyphenyl.

4. The 2-(1-oxo-7/-/-isoquinolin-2-yl)acetamide derivative according to any one of claims 1-3, wherein R⁴ is a substituent at the 7-position of the oxoisoquinoline ring.

5. The 2-(1-oxo-7/-/-isoquinolin-2-yl)acetamide derivative according to any one of claims 1-4, wherein R⁴ is a group selected from

wherein R⁶ and R⁷ have the previously defined meanings.

6. The 2-(1-oxo-7/-/-isoquinolin-2-yl)acetamide derivative according to any one of claims 1-4, wherein R⁴ is a group selected from

wherein R⁶ and R⁷ have the previously defined meanings.

7. The 2-(1-oxo-7/-/-isoquinolin-2-yl)acetamide derivative according to any one of claims 1-6, wherein R⁶ and R⁷ are independently H or d-₄alkyl.

8. The 2-(1-oxo-7/-/-isoquinolin-2-yl)acetamide derivative according to any one of claims 1-6, wherein R⁶ and R⁷ together with the nitrogen to which they are bonded form a heterocyclic ring selected from pyrrolidine, piperidine, 3-hydroxypiperidine and morpholine.

9. A 2-(1-oxo-7/-/-isoquinolin-2-yl)acetamide derivative selected from:

5 Λ/-terf-Butyl-2-[3-(4-fluoro-3-methoxyphenyl)-1-oxo-7-(3-pyrrolidin-1-ylpropoxy)-1 /-/- isoquinolin-2-yl]acetamide;

Λ/-terf-Butyl-2-[3-(3-chloro-4-fluorophenyl)-1-oxo-7-(3-pyrrolidin-1-ylpropoxy)-1 /-/- 10 isoquinolin-2-yl]acetamide or a pharmaceutically acceptable salt or solvate thereof.

10. A 2-(1-oxo-7/-/-isoquinolin-2-yl)acetamide derivative according to any one of claims 1- 9 for use in therapy.

15

1 1. A pharmaceutical composition comprising a 2-(1-oxo-7/-/-isoquinolin-2-yl)acetamide derivative according to any one of claims 1-9 in admixture with one or more pharmaceutically acceptable auxiliaries.

20 12. Use of a 2-(1-oxo-7/-/-isoquinolin-2-yl)acetamide derivative according to any one of claims 1-9 for the manufacture of a medicament for the treatment or prevention of disorders or diseases influenced by modulation of the activity of the HPA axis.

13. Use according to claim 12, wherein the medicament is for the treatment or prevention 25 of stress related disorders or depression.